Chromones (Cromolyn and Nedocromil)

Cromolyn is a synthetic substance derived from a natural plant product that has several important actions. Cromolyn was originally shown to inhibit the release of histamine from mast cells in vitro. Subsequently, it was demonstrated that inhaled cromolyn could inhibit exercise-induced bronchospasm, progressively decrease bronchial hyperactivity, and inhibit seasonal rises in bronchial hyperactivity in patients allergic to grass pollen. Cromolyn and nedocromil act at the surface of the mast cell and eosinophils to inhibit Ca⁺⁺ influx, thereby preventing the release of histamine and other inflammatory mediators. Cromolyn and nedocromil are active on the lung only when given by the inhaled route. They have no direct bronchodilator effect and thus are not useful for treating acute asthma attacks.

Glucocorticoids

The GCs have multiple actions that decrease inflammation in asthma, which is key to improving asthmatic symptoms and preventing exacerbations. In controlling the inflammation of asthma, the primary effect of the GCs is to alter gene expression. The GCs, through activation of GC receptors (see Chapter 39), suppress the expression of genes for many inflammatory proteins. Inflammation is mediated by the increased expression of multiple inflammatory proteins including cytokines, chemokines, adhesion molecules, and inflammatory enzymes and receptors. The expression of most of these inflammatory proteins is regulated by increased gene transcription, which is controlled by proinflammatory transcription factors. The GCs are believed to switch off only inflammatory genes and do not suppress all activated genes because of the selective binding to coactivators that are activated by proinflammatory transcription factors.

In addition to suppressing the synthesis of inflammatory mediators, the GCs also induce the transcription of several antiinflammatory proteins, including lipocortin, neural endopeptidase, and inhibitors of plasminogen activator. Lipocortin inhibits the activity of phospholipase A₂, thus decreasing the release of free arachidonic acid from phospholipids and reducing the subsequent production of leukotrienes and prostaglandins.

GCs decrease bone marrow production of eosinophils and enhance their removal from the circulation by mediating their adherence to capillary walls (margination). GCs also reduce the local accumulation of eosinophils by inhibiting the release of eosinophil chemotactic factors such as LTB₄ and cytokine tumor necrosis factor-α (TNF-α). The effect of the GCs on neutrophils is opposite to that on eosinophils. By inhibiting margination and stimulating bone marrow production, GCs lead to an increase in circulating neutrophils.

Leukotriene Modulators

The LTs are potent inflammatory mediators generated from the metabolism of arachidonic acid through the 5-lipoxygenase (5-LOX) pathway (Fig. 16-2). These compounds, along with prostaglandins and related compounds, belong to a group of substances termed the eicosanoids (see Chapter 15). The LTs are synthesized in many inflammatory cells in the respiratory system including eosinophils, mast cells, macrophages, and basophils and are responsible for mediating numerous asthmatic symptoms via stimulation of specific LT receptors. LTB₄ is a potent neutrophil chemotactic agent whose actions result from stimulation of members of the LTB receptor (BLT) family. Similarly, LTC₄ and LTD₄ cause bronchoconstriction, mucus hypersecretion, and mucosal edema and increase bronchial reactivity through activation of the Cys-leukotriene (CysLT, formerly known as the LTD₄) receptor family. The effects of the LTs can be modulated either by inhibiting LT biosynthesis or by blocking activation of CysLT receptors. Zileuton* is an inhibitor of 5-LOX, thereby decreasing LT synthesis, whereas zafirlukast and montelukast are antagonists at Cys-LT₁ receptors, thereby blocking receptor activation. These drugs are less effective antiinflammatory agents than the corticosteroids, but are preferable to long-term GC therapy because they have fewer adverse effects (see Chapter 39). They are used prophylactically in combination products.

FIGURE 16–2 Newly generated lipid mast cell mediators depicting the sites of action of the LTMs. Zileuton* inhibits 5-lipoxygenase, thereby inhibiting the synthesis of the leukotrienes, whereas zafirlukast and montelukast are antagonists at the CysLT₁ receptor. The inhibitory actions of the LTMs are shown in red.

Methylxanthines

Theophylline is a methylxanthine, pharmacologically similar to caffeine found in coffee and cola drinks. Theophylline exerts three actions, which may contribute to its usefulness as a bronchodilator. A major action of theophylline is as an adenosine receptor antagonist in bronchial smooth muscle. Adenosine acts as a natural bronchoconstrictor and increases histamine release from lung mast cells. Blocking these actions of endogenous adenosine could contribute to the antiinflammatory action of theophylline. The second action is theophylline inhibition of phosphodiesterase (PDE), increasing levels of cyclic adenosine monophosphate (cAMP), which lead to bronchodilation; however, the clinical significance of this mechanism has been questioned, because concentrations of theophylline required to inhibit this enzyme exceed those achieved with usual doses. The third proposed mechanism of theophylline involves its ability to activate histone deacetylase, an enzyme that functions to inhibit the acetylation of core histones required for the transcription of inflammatory genes. The ability of the methylxanthines to interact with ryanodine receptors to increase Ca⁺⁺ mobilization is important for the ability of these agents to enhance skeletal muscle strength, but not to their action in asthma.

Adrenergic β₂ Receptor Agonists

Stimulation of adrenergic β₂ receptors raises cAMP concentrations and inhibits smooth muscle contraction (see Chapter 9). Physiologically, bronchial smooth muscle relaxes, and the release of some mast cell-derived bronchoconstricting substances is inhibited. In addition, these drugs decrease microvascular permeability and suppress parasympathetic ganglionic activity (see Chapter 10). There is no evidence for an antiinflammatory effect of adrenergic agents or for any beneficial effect on bronchial hyperactivity.

Several β₂ receptor agonists have been used therapeutically for the treatment of asthma. Epi and isoproterenol are highly effective but are reserved for special circumstances because of their nonselective activity, leading to β₁ receptor-mediated cardiac stimulation. Short-acting selective β₂ receptor agonists include albuterol,¹ terbutaline, metaproterenol, bitolterol, and pirbuterol. Formoterol and salmeterol have been developed as highly lipid-soluble long-acting agents (t_1/2 = 12 hours).

Muscarinic Receptor Antagonists

Bronchial smooth muscle is innervated mainly by the parasympathetic nervous system, and its activation causes bronchoconstriction (see Chapter 9). Before the development of modern pharmacology, leaves from the belladonna plant, which contain muscarinic antagonists (atropine and scopolamine) were smoked as a treatment for asthma. Atropine can be used as a bronchodilator and to reduce secretions, but its use is limited by autonomic and central nervous system (CNS) adverse effects. Ipratropium bromide is a quaternary nitrogen derivative of atropine that does not cross the blood-brain barrier but competitively inhibits muscarinic acetylcholine receptors in bronchial smooth muscle (see Chapter 10). Ipratropium is used as an inhaled preparation. Tiotropium is a long-acting muscarinic antagonist used as a bronchodilator that is useful for patients with COPD.

Chromones

Both cromolyn and nedocromil act on inflammatory cells and neurons in the bronchial epithelium and are active only when inhaled, rendering plasma levels largely irrelevant. Cromolyn is very poorly absorbed from the gastrointestinal (GI) tract and has few systemic side effects because it is rapidly excreted. Although cromolyn has no direct bronchodilator activity and should not be used to treat an acute attack, it can be used to control exercise-induced bronchospasm, if administered 10 to 15 minutes before the onset of physical activity. In contrast to its rapid effect in controlling exercise-induced bronchospasm, long-term treatment with cromolyn or nedocromil requires several days or even weeks to produce an optimal antiinflammatory effect.

Glucocorticoids

The pharmacokinetics for the GCs are presented in Chapter 39. When used for the treatment of asthma or COPD, responses to inhaled or oral steroids can occur within 4 hours but may take as long as 2 weeks, depending on the nature of the underlying lung disorder.

Leukotriene Modulators

The LT receptor antagonists, montelukast and zafirlukast, as well as the 5-LOX inhibitor zileuton* are all orally administered, which is advantageous for treatment of children and other patients who have difficulty with or are noncompliant with inhaled therapies. Zileuton* has the disadvantage of requiring dosing four times per day. Montelukast and zafirlukast have similar pharmacokinetic profiles and may be administered once (montelukast) or twice (zafirlukast) daily. Zileuton* is also an inhibitor of hepatic CYP3A and will lead to increased levels of drugs metabolized by this CYP variant, including theophylline. This drug-drug interaction increases potential toxicity if the two drugs are administered concurrently.

Methylxanthines

Theophylline clearance is influenced by food, smoking, age, disease, and other drugs metabolized by the liver (Table 16-2). Monitoring serum theophylline concentrations is necessary for any patient taking more than a minimal dose orally, especially sustained-release formulations, because of the multiple factors that influence blood concentrations and because the range of safe therapeutic concentrations is narrow. The therapeutic range is 5 to 15 µg/mL, and serious toxicity is increasingly likely at blood concentrations greater than 20 µg/mL, which results in a low therapeutic index.

When administered intravenously, theophylline can act rapidly on the lungs as a bronchodilator. However, this requires large bolus doses, which are used only occasionally because of toxicity. It is easier to maintain therapeutic blood concentrations by the oral route using sustained-release preparations, but this approach can lead to problems of cumulative toxicity.

Adrenergic β₂ Receptor Agonists

A general comparison of the pharmacokinetic profiles for these compounds is presented in Table 16-3. The bronchodilation that occurs in response to inhaled β₂ receptor agonists has a fairly consistent onset at 5 to 30 minutes. Tightness of the chest will abate in most patients with asthma within 10 minutes after an injection of Epi. An optimal effect usually occurs within an hour and may last for 2 to 4 hours. In most circumstances β₂ receptor agonists are effective for approximately 4 to 6 hours. Prolonged, repeated use of short-acting β₂ receptor agonists, however, can cause a significant increase in heart rate in a small proportion of patients as a result of systemic absorption and concomitant stimulation of cardiac β₁ receptors. With the development of a longer-acting β₂ receptor agonist (salmeterol), which lasts for more than 12 hours, this problem may be partially resolved. However, unlike the short-acting β receptor agonists, salmeterol is not effective in treating acute episodes. Its major uses are in controlling nocturnal asthma and some cases of exercise-induced bronchospasm. The use of salmeterol alone has been associated with an increased risk of severe asthma exacerbations. Therefore it has been recommended that this agent be taken in fixed-dose combinations with an inhaled corticosteroid.

Muscarinic Receptor Antagonists

Inhaled ipratropium bromide is poorly absorbed and has few systemic side effects. The peak bronchodilator effect occurs 1 to 2 hours after inhalation, with a duration of action of 3 to 5 hours (see Table 16-3). Tiotropium, which exhibits selectivity at M₁ and M₃ receptors (see Chapter 10), has a duration of action of 24 hours. Both of these agents are used for management of the bronchoconstrictive component of COPD.

Outpatient Treatment of Asthma

In a patient with occasional wheezing, a diagnosis must be established by demonstrating a reversible airway obstruction and having the patient use a peak-flow meter at home for 2 weeks. Treatment involves using a β₂ receptor agonist, two puffs by MDI when necessary. In a patient with exercise-induced bronchospasm, it is imperative to show that breathlessness after exercise is associated with airway obstruction. Recommended treatments to prevent exercise-induced bronchospasm are an inhaled β₂ receptor agonist, two puffs 5 to 10 minutes before exercise, or two puffs of cromolyn Na⁺ by MDI 10 to 20 minutes before exercise, or one puff of salmeterol by MDI 30 to 60 minutes before exercise. Inadequate control requires identifying the causes of the bronchial hyperactivity. Leukotriene antagonists are effective as prophylactic agents.

In a patient who is suffering more frequent symptoms, including nocturnal asthma, or who is using a short-acting β₂ receptor agonist more than three times per week, documentation of reversible airway obstruction is of paramount importance. This can be achieved by: (a) measuring changes in PEF or FEV₁ before and after administration of the bronchodilator; (b) demonstrating a 15% to 20% increase in PEF or FEV₁ after bronchodilator administration; or (c) demonstrating hyper-reactivity to inhaled histamine, methacholine, or cold air. Skin tests should be used to identify relevant sensitivities to allergens. If a patient has positive skin test results, then education relevant to decreasing exposure to the specific allergens is a first step in management. These patients may benefit from the combination of a long-acting β₂ receptor agonist, in combination with a leukotriene antagonist. Short-acting bronchodilators should be reserved for the reversal of acute episodes.

Inhaled corticosteroids, cromolyn, or nedocromil, taken on a regular basis, should be prescribed for any patient who continues to have symptoms necessitating bronchodilator therapy more than three times weekly. If symptoms persist and spirometry confirms obstruction, the dose of the antiinflammatory agent should be increased, and an oral delayed-release theophylline preparation, 200 to 300 mg two or three times a day, should be considered. After 4 days the theophylline blood concentrations should be from 5 to 14 µg/mL.

For acute asthmatic episodes, doses of inhaled steroids should be increased to four puffs four times a day and theophylline added as needed. A short course of oral steroids (60 mg of prednisone reduced to zero over 6 to 8 days) may also be necessary. In the clinic or emergency room, a nebulized β₂ receptor agonist is the first line of treatment, which can be repeated three times at 20-minute intervals, and then hourly thereafter. Patients not responding to nebulizer treatment should receive steroids (60 mg of prednisone or 125 mg of methylprednisolone IV).

Patients with unresponsive persistent symptoms may be treated with regular-dose, inhaled steroids four puffs four times a day, theophylline up to a maximum therapeutic range, and additional drugs, including cromolyn or nedocromil, a β₂ receptor agonist delivered by nebulizer, or an LTM. Courses of oral steroids (6 to 30 days) and other agents may also be considered. The physician should reinforce education on allergen avoidance and consider other factors such as diet, fungal infections, drug reactions, sinusitis, and gastroesophageal reflux.

Antihistamines are generally not recommended for treatment of asthma. However, many allergic patients with rhinitis and asthma use antihistamines with no apparent harmful effects. Sedative antihistamines (see Chapter 14) should not be used in patients with acute bronchospasm. Antibiotics are commonly recommended for management of an exacerbation of asthma because of sputum production but should be reserved for those patients with bronchial infiltrates, fever, or sinusitis.

Allergen Avoidance

Exposure to allergens, particularly those found indoors, is well recognized as an important cause of asthma. Identification of sensitivity and education about measures necessary to decrease exposure are an important part of antiinflammatory treatment. For control of dust mites, enclosing the mattress and pillows in dust mite-proof covers, washing all bedding in boiling H₂O, removing carpets, and using air filtration systems are important measures. Removing cats or dogs from the environment may be helpful; however, it will take weeks or months for the associated allergen levels to decrease. Cockroach eradication may be important for inner-city homes, in particular, and should involve such measures as enclosing all food, sealing gaps around pipes, and using poisonous bait. Special issues related to asthma are discussed in Box 16-1.

Chromones

The side effects of cromolyn and nedocromil are restricted to the irritant effects of inhaling the drugs. There is very little convincing evidence for short-term or long-term drug toxicity and no recognized blood concentration that is toxic. Occasional cases of dermatitis, gastroenteritis, and myositis that are apparently associated with cromolyn use have been reported but are very unusual.

Glucocorticoids

The side effects of systemic corticosteroids are discussed in Chapter 39 and are mentioned here briefly in the context of pulmonary disease. The most important issue is the difference between short- and long-term use. Treatment with high-dose steroids, even short-term, can cause hypertension, diabetes, GI bleeding, and CNS disturbances. Elevations in blood glucose concentration and emotional changes are common but are usually easy to manage. Long-term steroid use produces a wide range of severe side effects, including thinning of the skin (striae, bruising), osteoporosis with rib fractures and vertebral compression, aseptic necrosis of the femoral head, which usually presents with pain, diabetes with complications, GI discomfort, ulceration and bleeding, cataract formation, and CNS disturbances, including frank psychosis. Prolonged oral use of steroids causes profound suppression of adrenal function. If patients are taking oral steroids for more than 7 days, the dose should be gradually reduced, because abrupt withdrawal can result in life-threatening adrenal insufficiency. Patients must be made fully aware of the harmful effects of long-term orally administered steroids.

Although there was concern that inhaled steroids would produce serious side effects in the lungs or systemically, this is not the case. The major side effects of inhaled steroids (e.g., beclomethasone dipropionate) have been oral candidiasis and occasionally irritation triggered by the use of an MDI. In all patients, but especially those with COPD, yeast infection of the mouth (thrush) is common and requires local treatment. The efficacy of chronic use of inhaled steroids in patients with COPD is not well established, because the possibility exists that inhaled steroids might encourage fungal colonization in patients with a severe fixed obstruction, that is, FEV₁ <40% predicted.

In contrast, large doses of inhaled corticosteroids have significant effects on the adrenal axis and bone growth in children. Inhaled steroids are all active locally, and their systemic side effects depend on both absorption and metabolism. There is some evidence that budesonide and flunisolide have fewer systemic effects because their metabolites are inactive.

Leukotriene Modulators

Adverse effects of the leukotriene antagonists zafirlukast and montelukast are minimal, and generally, the drugs are well tolerated. However, rare cases of hepatotoxicity and eosinophilic vasculitis have occurred. The clinical features of the vasculitis are consistent with Churg-Strauss syndrome, a life-threatening condition typically treated with systemic corticosteroid therapy. The occurrence of the vasculitis syndrome appears to be linked with the decrease or withdrawal of oral corticosteroid therapy. Therefore the patient and the physician need to be acutely aware of symptoms related to eosinophilia, vasculitic rash, worsening of pulmonary symptoms, cardiac complications, and developing neuropathies.

Zileuton* can produce elevated liver enzymes, typically in the first few months of therapy. It also inhibits hepatic CYP3A, which metabolizes many drugs, including theophylline. Considering the correlation of serum levels of theophylline to therapeutic and toxic effects, patient monitoring is necessary if the two drugs are used concurrently.

Methylxanthines

The most common side effects of theophylline that can occur within the normal therapeutic range are either GI upset (e.g., heartburn, abdominal pain, nausea, vomiting) caused by an increase in gastric acidity or CNS effects including headache, anxiety, tremor, and insomnia (similar to those reported with excess use of caffeine). Side effects occur with concentrations as low as 5 µg/mL but increase greatly in frequency and severity when the blood concentrations of theophylline exceed 15 µg/mL (the recommended upper limit). When blood concentrations exceed 20 µg/mL, seizures and cardiac dysrhythmias are possible and become common when blood concentrations exceed 35 µg/mL. Seizures can result in significant mortality; thus elevated theophylline concentrations are treated as an emergency with gastric lavage, oral charcoal, and even dialysis. Considerable attention has been given to CNS symptoms in children receiving methylxanthines, including poor attention and insomnia, with resultant poor school performance.

Adrenergic β₂ Receptor Agonists

The primary side effects of adrenergic agonists are cardiac stimulation, hypertension, tremor, and restlessness (see Chapter 11). The use of selective β₂ receptor agonists decreases the risk of some of these effects. Inhaled β₂ receptor agonists generally produce fewer side effects than oral preparations. Nonetheless, tachycardia and muscle tremor still occur. Continued use of these agents may result in the desensitization of β receptors (see Chapter 1); however, GC therapy can prevent or partially reverse this phenomenon. Epi can ameliorate severe life-threatening asthma attacks when administered subcutaneously. However, there are very few indications for this form of treatment in older patients or in those with underlying cardiovascular disease. Although there was a concern that chronic use of short-acting β₂ receptor agonists would worsen asthma, this has not proven to be the case.

Muscarinic Receptor Antagonists

Inhaled ipratropium or tiotropium may give rise to drying of the mouth and upper airways. Because these drugs are administered via inhalation, systemic adverse effects,

such as those associated with atropine, are unusual (see Chapter 10).